Method for treating glaucoma

Abstract

Methods of using prostaglandin agonists for the reduction of intraocular pressure, and accordingly glaucoma.

What is claimed is:  
     
       1. A method for reducing intraocular pressure in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1:                    
       or a pharmaceutically acceptable salt or prodrug thereof wherein either (i): 
       B is N;  
       A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 7 )cycloalkylsulonyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di- or tri- substituted on carbon independently with hydroxy, (C 1 -C 4 )alkyl or halo,  
       Q is  
       —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-,  
       —(C 3 -C 8 )alkylene-, said —(C 3 -C 8 )alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4 )alkyl,  
       —X—(C 1 -C 5 )alkylene-,  
       —(C 1 -C 5 )alkylene-X—,  
       —(C 1 -C 3 )alkylene-X—(C 1 -C 3 )alkylene-,  
       —(C 2 -C 4 )alkylene-W—X—(C 0 -C 3 )alkylene-,  
       —(C 0 -C 4 )alkylene-X—W—(C 1 -C 3 )alkylene-,  
       —(C 2 -C 5 )alkylene-W—X—W—(C 1 -C 3 )alkylene-, wherein the two occurrences of W are independent of each other,  
       —(C 1 -C 4 )alkylene-ethenylene-(C 1 -C 4 )alkylene-,  
       —(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X—(C 0 -C 5 )alkylene-,  
       —(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X—W—(C 1 -C 3 )alkylene-,  
       —(C 1 -C 4 )alkylene-ethynylene-(C 1 -C 4 )alkylene-, or  
       —(C 1 -C 4 )alkylene-ethynylene-X—(C 0 -C 3 )alkylene.  
     
     
       2. The method as recited in  claim 1  wherein 
       B is N;  
       A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl or (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro;  
       X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;  
       W is oxy, thio or sulfonyl;  
       Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;  
       K is methylene;  
       Ar, Ar 1  and Ar 2  are each independently (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;  
       R 1  is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and  
       R 2  and R 3  are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.  
     
     
       3. The method as recited in  claim 2  wherein 
       A is (C 1 -C 3 )alkylsulfonyl;  
       Q is  
       —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-,  
       —(C 4 -C 8 )alkylene-, said —(C 4 -C 8 )alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4 )alkyl,  
       —(C 1 -C 5 )alkylene-X—,  
       —(C 1 -C 3 )alkylene-X—(C 1 -C 3 )alkylene-, or  
       —(C 0 -C 4 )alkylene-X—W—(C 1 -C 3 )alkylene-,  
       M is —Ar 1 —V—Ar 2  or —Ar 1 —O—Ar 2  wherein Ar 1  and Ar 2  are each independently phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazinyl, pyrrazolyl, pyradizinyl or thienyl;  
       V is a bond or (C 1 -C 2 )alkylene;  
       R 1  is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and  
       R 2  and R 3  are each independently chloro or fluoro.  
     
     
       4. The method as recited in  claim 1  wherein 
       B is N;  
       A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl;  
       Q is  
       —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-,  
       —(C 4 -C 8 )alkylene-, said —(C 4 -C 8 )alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4 )alkyl,  
       —(C 1 -C 5 )alkylene-X—,  
       —(C 1 -C 3 )alkylene-X—(C 1 -C 3 )alkylene-, or  
       —(C 0 -C 4 )alkylene-X—W—(C 1 -C 3 )alkylene-,  
       X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;  
       W is oxy, thio or sulfonyl;  
       Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;  
       K is (C 1 -C 8 )alkylene or oxy(C 2 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;  
       M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;  
       R 1  is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 —C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted  
       independently with hydroxy, fluoro or chloro; and  
       R 2  and R 3  are each independently hydroxy, halo, trifluoromethyl, (C 1 -C 7 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 5 )alkanoyl, cyano, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 cycloalkyl(C 1 -C 4 )alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl. 
     
     
       5. The method as recited in  claim 4  wherein 
       A is (C 1 -C 3 )alkylsulfonyl;  
       K is oxy(C 2 -C 4 )alkylene;  
       —Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and  
       R 1 , R 2  and R 3  are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.  
     
     
       6. The method as recited in  claim 4  wherein the compound is 
       7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid,  
       5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or  
       N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.  
     
     
       7. The method as recited in  claim 4  wherein 
       Q is —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-; and  
       W is oxy.  
     
     
       8. The method as recited in  claim 4  wherein 
       Q is —(C 3 -C 8 )alkylene-, said —(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.  
     
     
       9. The method as recited in  claim 8  wherein 
       A is methylsulfonyl;  
       Q is n-hexylene;  
       Z is carboxyl;  
       K is oxyethylene; and  
       M is 3,5-dichlorophenyl.  
     
     
       10. The method as recited in  claim 4  wherein 
       Q is —(C 1 -C 5 )alkylene-X—; and  
       X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.  
     
     
       11. The method as recited in  claim 10  wherein 
       A is methylsulfonyl;  
       Q—Z is 3-(2-carboxylthien-5-yl)-n-propylene;  
       K is oxyethylene; and  
       M is 3,5-dichlorophenyl.  
     
     
       12. The method as recited in  claim 1  wherein glaucoma is treated in a human. 
     
     
       13. The method as recited in  claim 12  wherein about 0.01 mg/kg/day to about 10 mg/kg/day of the Formula I compound is administered. 
     
     
       14. The method as recited in  claim 13  wherein the Formula I compound is administered topically. 
     
     
       15. The method as recited in  claim 14  wherein 
       B is N;  
       A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl or (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro;  
       X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;  
       W is oxy, thio or sulfonyl;  
       Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;  
       K is methylene or ethylene;  
       Ar, Ar 1  and Ar 2  are each independently (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;  
       R 1  is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and  
       R 2  and R 3  are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.  
     
     
       16. The method as recited in  claim 15  wherein 
       A is (C 1 -C 3 )alkylsulfonyl;  
       Q is  
       —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-,  
       —(C 4 -C 8 )alkylene-, said —(C 4 -C 8 )alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4 )alkyl,  
       —X—(C 2 -C 5 )alkylene-,  
       —(C 1 -C 5 )alkylene-X—,  
       —(C 1 -C 3 )alkylene-X—(C 1 -C 3 )alkylene-,  
       —(C 2 -C 4 )alkylene-W—X—(C 0 -C 3 )alkylene-, or  
       —(C 0 -C 4 )alkylene-X—W—(C 1 -C 3 )alkylene-;  
       M is —Ar 1 —V—Ar 2  or —Ar 1 —O—Ar 2  wherein Ar 1  and Ar 2  are each independently phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazinyl, pyrrazolyl, pyradizinyl or thienyl;  
       V is a bond or (C 1 -C 2 )alkylene;  
       R 1  is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and  
       R 2  and R 3  are each independently chloro or fluoro.  
     
     
       17. The method as recited in  claim 14  wherein 
       B is N;  
       A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl;  
       X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;  
       W is oxy, thio or sulfonyl;  
       Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;  
       K is (C 1 -C 8 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;  
       M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;  
       R 1  is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted  
       independently with hydroxy, fluoro or chloro; and  
       R 2  and R 3  are each independently hydroxy, halo, trifluoromethyl, (C 1 -C 7 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 5 )alkanoyl, cyano, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl. 
     
     
       18. The method as recited in  claim 17  wherein 
       A is (C 1 -C 3 )alkylsulfonyl;  
       K is oxy(C 1 -C 4 )alkylene;  
       —Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and  
       R 1 , R 2  and R 3  are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.  
     
     
       19. The method as recited in  claim 17  wherein the compound is 
       7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid,  
       5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or  
       N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.  
     
     
       20. The method as recited in  claim 14  wherein 
       Q is —(C 2 -C 6 )alkylene-W—(C 1 -C 3 )alkylene-; and  
       W is oxy.  
     
     
       21. The method as recited in  claim 14  wherein 
       Q is —(C 3 -C 8 )alkylene-, said —(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.  
     
     
       22. The method as recited in  claim 21  wherein 
       A is melthylsulfonyl;  
       Q is n-hexylene;  
       Z is carboxyl,  
       K is oxyethylene; and  
       M is 3,5-dichlorophenyl.  
     
     
       23. The method as recited in  claim 14  wherein 
       Q is —(C 1 -C 5 )alkylene-X—; and  
       X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.  
     
     
       24. The method as recited in  claim 23  wherein 
       A is methylsulfonyl;  
       Q—Z is 3-(2-carboxylthien-5-yl)-n-propylene;  
       K is oxyethylene; and  
       M is 3,5-dichlorophenyl.